Infertility affects ~70 million married couples around the world;half of the cases are attributed to male factors for which the cause is poorly understood and the treatment is extremely limited. On the other hand, novel male contraceptives are needed because very few options are available for males and nearly half of all pregnancies in the United States are unintended. Understanding the spermatogenic cycle has important clinical relevance, because disruption of the process leads to infertility or subfertility, and being able to regulate the process would provide new avenues to male contraceptives. The spermatogenic cycle describes the periodic development of male germ cells in the testicular tissue. The temporal-spatial dynamics of the cycle highlights the unique, complex, and interdependent interaction between germ and somatic cells, and is the key to successful continual production of sperm. However, the precise action of germ cells that leads to the emergence of testicular tissue patterns remains uncharacterized. We hypothesize that the periodic patterning of germ cells results from multiple cellular behaviors including feedback regulation, mitotic and meiotic division, differentiation, apoptosis, and movement, and that genetic and environmental perturbations cause the altered arrangement of the developing germ cells through disruption of these cellular behaviors. The goal of this project is to develop a computer model to simulate the mouse spermatogenic cycle on a cross-section of the seminiferous tubule over a time scale of hours to years. By manipulating cellular behaviors either individually or collectively in silico, the model will allow us to predict the causal eventsto the normal and abnormal testicular morphology. Mouse data, published and generated herein, will be used to develop our computer model and to test its predictive capabilities. The proposed computer model will elaborate the temporal-spatial dynamics of germ cells in a time-lapse movie format, allowing us to trace individual cells as they change state and location. More importantly, the model provides a mechanistic understanding of the fundamentals of male fertility, namely, how testicular morphology and continuous sperm production are achieved. The long-term goals of this project are to integrate knowledge about reproductive system dynamics into a realistic computer model that encompasses spatial scales of molecular, cellular, and tissue events occurring over a time scale of minutes to years and to use this model to identify optimal approaches for infertility treatment and contraceptive development.

Public Health Relevance

Using a systems biology approach, we will simulate the spermatogenic cycle on a temporal-spatial scale and present the results in a time-lapse movie format. This project will yield an interactive tool to study the role of cellular behaviors in the arrangement of germ cells and the timing of sperm release. Such knowledge will be critical when treating male infertility or developing male contraceptives.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD079723-01
Application #
8680089
Study Section
Developmental Biology Subcommittee (CHHD)
Program Officer
Moss, Stuart B
Project Start
2014-05-01
Project End
2016-03-31
Budget Start
2014-05-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
Pullman
State
WA
Country
United States
Zip Code
99164
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Whitmore, Leanne S; Ye, Ping (2015) Dissecting Germ Cell Metabolism through Network Modeling. PLoS One 10:e0137607
Grandi, Fiorella C; Rosser, James M; Newkirk, Simon J et al. (2015) Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites. Genome Res 25:1135-46
Ray, Debjit; Pitts, Philip B; Hogarth, Cathryn A et al. (2014) Computer simulations of the mouse spermatogenic cycle. Biol Open 4:1-12